Bile acids and acetaminophen protein adducts in children with acetaminophen overdose (653.1)

Abstract

Disruption of bile acid transport is a recognized mechanism of drug induced liver injury. The relationship of circulating bile acids to acetaminophen protein adducts and to alanine aminotransferase (ALT) levels was examined in healthy controls and children hospitalized for acetaminophen overdose. Mean (range) peak values of ALT and adducts for controls (23) and overdose (64) were ALT: 18 (10‐37 IU/L) vs. 626 (8‐9909 IU/L) and adducts: 0.01 (0‐0.01 nmol/mL) vs. 0.72 (0.03‐7.92 nmol/mL). Mean (range) time to treatment with N‐acetylcysteine for overdose subjects was 15 (1‐85 h). Targeted analysis of nine bile acids using UPLC/TQ‐MS showed that Glycocholic Acid (GCA), Glycodeoxycholic Acid (GDCA), and Taurodeoxycholic Acid (TDCA) were higher in children with APAP overdose (p<0.001) compared to controls. ROC analysis of bile acids showed that GDCA was the best discriminator of APAP overdose (ROC AUC=0.861 [95% CI: 0.758 ‐ 0.964] compared to controls). GDCA > 0.364 uM distinguished APAP overdose from controls (sensitivity 93.8%, specificity 68.4%). Comparison of time to achieve peak values was examined for adducts, bile acids and ALT. Adducts peaked prior to ALT (p=0.057) and bile acids (p<0.001) and ALT peaked prior to GDCA and TDCA (p=0.001). Bile acids are increased in children with APAP overdose compared to controls and GDCA is the best predictor of APAP overdose among the bile acids examined.